The relationship between pan-immune-inflammation value and survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab in the second line and beyond: a Turkish oncology group kidney cancer consortium (TKCC) study

Pan-immune-inflammation value (PIV) is an easily accessible immune marker based on peripheral blood to estimate prognosis in patients with cancer. This study evaluates the prognostic value of PIV in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. In this retrospective cohort study, patients with mRCC treated with nivolumab in the second line and beyond were selected from the Turkish Oncology Group Kidney Cancer Consortium (TKCC) database. PIV was calculated using the following formula: neutrophil (103/mm3) x monocyte (103/mm3) x platelet (103/mm3)/lymphocyte (103/mm3). A total of 152 patients with mRCC were included in this study. According to cut-off value for PIV, 77 (50.7%) and 75 (49.3%) patients fell into PIV-low (≤\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\le$$\end{document} 372) and PIV-high (> 372) groups, respectively. In multivariate analysis, PIV-high (HR: 1.64, 95% CI 1.04–2.58, p = 0.033 for overall survival (OS); HR: 1.55, 95% CI 1.02–2.38, p = 0.042 for progression-free survival (PFS)) was independent risk factor for OS and PFS after adjusting for confounding variables, such as performance score, the International mRCC Database Consortium (IMDC) risk score, and liver metastasis. This study established that pre-treatment PIV might be a prognostic biomarker in patients with mRCC treated with nivolumab in the second line and beyond.


Introduction
Treatment options in metastatic renal cell carcinoma (mRCC) have been expanding over the last decade. Antivascular endothelial growth factor (VEGF) targeted therapies (TTs), immune checkpoint inhibitors (ICIs), and combinations of TTs and ICIs are the mainstay of treatment in patients with mRCC. (Choueiri et al. 2021;Motzer et al. 2021;Motzer et al. 2015;Motzer et al. 2018;Posadas et al. 2017) Nivolumab is a human immunoglobulin G4 programmed death-1 (PD-1) ICI antibody. The CheckMate 025 trial showed the superiority of nivolumab to everolimus in patients with mRCC previously treated with anti-VEGF TTs. After this trial, the Food and Drug Administration (FDA) approved an ICI, nivolumab, for the first time in the treatment of mRCC. (Motzer et al. 2015;Xu et al. 2017).
It is well known that inflammation plays a crucial role in tumor pathogenesis and response to treatment with anticancer drugs. (Grivennikov et al. 2010) In fact, peripheral blood cells, such as neutrophils, platelets, lymphocytes, and monocytes, are the main indicators of tumor-associated inflammation. (Dymicka-Piekarska et al. 2021) In this context, neutrophils, monocytes, and platelets contribute to the tumor progression, while lymphocytes fight against cancer. (Grivennikov et al. 2010;Laubli et al. 2009;Mantovani et al. 2008;Wu et al. 2019) Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are the commonly investigated immune-inflammatory biomarkers (IIBs), which are calculated using the peripheral blood parameters, such as neutrophils, lymphocytes, monocytes, and platelets. Numerous studies showed their prognostic values in solid tumors (Gao et al. 2019;Liu et al. 2019;Vicente Conesa et al. 2012;Wang and Zhu 2019) and renal cell carcinoma (RCC) (Garcia-Rojo et al. 2021;Hizal et al. 2020;Na et al. 2016;Templeton et al. 2016;Yasar et al. 2020).
Pan-immune-inflammation value (PIV) is a new composite biomarker to predict inflammation status in cancer patients. It was reported for the first time in patients with metastatic colorectal cancer (mCRC). (Fuca et al. 2020) After this study, its prognostic value was shown in patients with malign melanoma, breast cancer, Merkel cell carcinoma and mCRC treated with ICIs. (Corti et al. 2021;Fuca et al. 2021;Gambichler et al. 2022;Ligorio et al. 2021;Susok et al. 2022) Unlike the other peripheral blood IIBs, as mentioned before, it is calculated using the four peripheral blood cells, such as neutrophil, lymphocyte, monocyte, and platelet. To date, no study assessed the prognostic value of PIV among patients with mRCC.
In this study, we aimed to evaluate the prognostic value of PIV in patients with mRCC treated with nivolumab in the second line and beyond.

Patients and data collection
Turkish Oncology Group Kidney Cancer Consortium (TKCC) is a multi-center registry consisting of 13 cancer centers in Turkey. In this retrospective study, we selected patients with mRCC treated with nivolumab in the second line and beyond from the TKCC database. After excluding 21 patients due to missing laboratory values for PIV, we included 152 patients in this study. The flowchart of patient selection is shown in Fig. 1.
This study was approved by the local ethical committee and conducted in accordance with the "Declaration of Helsinki".

Statistical analysis
Median (interquartile range (IQR)) or mean ± standard deviation (SD) for continuous variables and percentages for categorical variables was used to describe the data. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. PIV was calculated using the following formula as described previous studies (Corti et al. 2021): neutrophil (10 3 /mm 3 ) x monocyte (10 3 /mm 3 ) x platelet (10 3 /mm 3 )/ lymphocyte (10 3 /mm 3 ). Laboratory values for calculating PIV were obtained from the laboratory results in the last week before the initiation of nivolumab. A cut-off value for PIV was calculated by the using the maximally selected rank statistics method for overall survival (OS). Patients were divided into two groups as PIV-low ( ≤ 372) and PIVhigh (> 372).
OS was calculated from initiation of nivolumab to death and PFS was calculated from initiation of nivolumab to disease progression or death, whichever first occurred. Kaplan-Meier estimates were used for survival analyses. A log-rank test was performed to compare survival curves. Cox's proportional hazard regression models were used for multivariate analysis of OS and PFS. To estimate independent variables for OS and PFS, regression models were constructed using the statistically significant variables in univariate survival analyses. A p value less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 27.0 for Mac (IBM Corp., Armonk, NY) and R Studio (version 1.4.1106) with survminer, maxstat, and ggsurvplot packages.

Patient characteristics
A total of 152 patients with mRCC were included in this study. The median age was 60 years (IQR: 54-67 years). Most patients were male (77%), had clear cell histology (82.2%), and underwent nephrectomy (77%). The sarcomatoid feature was observed in 18 patients (11.8%). Approximately half of the patients received nivolumab in the second line, while the remaining patients received the third line and beyond. There were 13 (8.6%), 94 (61.8%), and 23 (

Discussion
In this study, we established that pre-treatment PIV was an independent prognostic factor in patients with mRCC treated with nivolumab in the second line and beyond. To the best of our knowledge, this was the first study assessing the prognostic value of PIV in patients with mRCC treated with nivolumab.
In fact, the easy access to peripheral blood IIBs makes them more attractive for use as a prognostic biomarker. To date, many studies evaluated the prognostic value of NLR and SII in patients with mRCC. (Hizal et al. 2020;Rebuzzi et al. 2020;Teishima et al. 2020) However, a few studies assessed these biomarkers in patients with mRCC treated with ICIs. One of these studies showed that NLR was a prognostic factor for OS and PFS in patients with mRCC treated with nivolumab. However, a small sample size (n = 38) was an important limitation of this study. (Bilen et al. 2018) Similarly, in another study including a small number of patients (n = 42), Jeyakumar et al. showed that pre-treatment NLR was an independent prognostic factor for OS and PFS in patients with mRCC treated with ICIs. (Jeyakumar et al. 2017) On the other hand, Lalani et al. concluded that not only pre-treatment NLR but also change in NLR during the treatment period was associated with survival outcomes. (Lalani et al. 2018) In contrast to these studies, Nishiyama et al. established that baseline NLR was not associated with survival outcomes in patients with mRCC treated with nivolumab. (Nishiyama et al. 2020).
Composite biomarkers, such as NLR, PLR, and lymphocyte-to-monocyte (LMR), include only two parameters, while SII consists of three parameters (i.e., neutrophil, platelet, and lymphocyte). The conflicting results mentioned above may be associated with the parameters used to calculate peripheral blood IIBs. At that point, a question arises in terms of whether the effect of more parameters may increase the prognostic value of composite biomarkers. Interestingly, a study comparing the LMR and SII showed that SII was an independent prognostic factor, while LMR had no impact on survival outcomes after adjusting for confounding factors. (Rebuzzi et al. 2020) In another study, De Giorgi et al. showed that SII was superior to NLR in prognostic value. (De Giorgi et al. 2019) On the other hand, the pivotal study of PIV showed that PIV had a greater relative influence on OS and PFS than NLR and SII in patients with mCRC. (Fuca et al. 2020) Taken together, including four parameters (i.e., neutrophil, monocyte, platelet, and lymphocyte) of PIV might contribute to the prognostic value on patients with mRCC treated with nivolumab in the second line and beyond.
The IMDC risk score is a well-known prognostic tool in patients with mRCC. It is composed of six parameters, including two peripheral blood IIBs (i.e., neutrophil and platelet). (Heng et al. 2009) However, it was not an independent prognostic factor in multivariate analysis in our study. Similar to our results, a study of De Giorgi et al., which was evaluated the SII in patients with mRCC treated with nivolumab, established that the IMDC risk score was not an independent prognostic indicator, while SII was prognostic for survival outcomes in multivariate analysis. (De Giorgi et al. 2019) The IMDC risk score is used to stratify patients with mRCC before the initiation of the first-line treatment. (National Comprehensive Cancer Network-Kidney Cancer 2021) Furthermore, studies showed that the IMDC risk score was a prognostic indicator in patients with mRCC treated with nivolumab in the second line. (Dudani et al. 2020;Yip et al. 2018) Interestingly, our study suggested that PIV might be a better option than the IMDC risk score to guide the prognosis in patients with mRCC treated with nivolumab in the second line and beyond.   The rate of patients treated with nivolumab in the second line was higher in the PIV-low group than in the PIV-high group. However, no statistically significant was observed in survival outcomes between the patients receiving nivolumab in the second line and those receiving it in the third line and beyond.
In this study, we have several limitations. One of the most important limitations of our study was based on its retrospective nature. With this regard, PFS was not appropriately assessed by cross-sectional imaging in the prespecified intervals. Furthermore, we had to exclude patients with missing data because of the retrospective feature of our study. Additionally, our study was a multi-center study, and it might have led to variations in laboratory values and imaging methods. To mitigate the impact of variations on laboratory values, we included only laboratory data collected in the last week before the initiation of nivolumab. Laboratory values that were used to calculate PIV might have been affected by any other conditions, such as infections, steroid use, smoking, etc. It was not possible to retrospectively evaluate the existence of these factors.

Conclusion
In conclusion, our study showed that PIV might be an easily accessible composite biomarker in patients with mRCC treated with nivolumab in the second line and beyond.
Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.